Evaluation of β-Aminocarboxylic Acid Derivatives in Hippocampal Excitatory Synaptic Transmission

Article abstract of DOI:10.1002/ardp.201700179

β-Aminocarboxylic acid derivatives (LINS04 series) were screened with the aim to explore their potential functional role in excitatory synaptic transmission in the central nervous system. We used field recordings in rat hippocampal slices to investigate the effects of the LINS04 series on the synaptic transmission at hippocampal CA1 synapses. We found that LINS04008 and LINS04009 increase the size of the evoked field excitatory postsynaptic potential (EPSP) in a dose-dependent manner. The concentration–response curve shows that the efficacy of LINS04008 is highest in the series (EC₅₀ = 91.32 μM; maximum fEPSP 44.97%). The esters LINS04006 and LINS04005 did not affect the synaptic evoked activity. These data provide the first evidence of synaptic activity enhancement by these compounds and the importance of the acidic group to the activity. This set of data may provide direction for a strategic procedure to restore the glutamate synaptic transmission; however, further studies are needed to establish a more complete picture of how these molecules act on the glutamate transmission, which are in our mind for the next steps.

Full text of DOI:10.1002/ardp.201700179

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Full Paper
Evaluation of b-Aminocarboxylic Acid Derivatives in Hippocampal
Excitatory Synaptic Transmission
2
1
2
Daniela R. Oliveira1 , Cibele V. Luchez , Zuner A. Bortolotto , and Joao P. S. Fernandes
ꢀ
~
1
Centre for Synaptic Plasticity, School of Physiology, Pharmacology and Neuroscience University of
Bristol, Bristol, UK
Departamento de Ciencias Farmaceuticas, Universidade Federal de Sao Paulo, Diadema-SP, Brazil
2
^
^
~
b-Aminocarboxylic acid derivatives (LINS04 series) were screened with the aim to explore their
potential functional role in excitatory synaptic transmission in the central nervous system. We used
field recordings in rat hippocampal slices to investigate the effects of the LINS04 series on the
synaptic transmission at hippocampal CA1 synapses. We found that LINS04008 and LINS04009 increase
the size of the evoked field excitatory postsynaptic potential (EPSP) in a dose-dependent manner.
The concentration–response curve shows that the efficacy of LINS04008 is highest in the series
(EC50 ¼ 91.32 mM; maximum fEPSP 44.97%). The esters LINS04006 and LINS04005 did not affect the
synaptic evoked activity. These data provide the first evidence of synaptic activity enhancement by
these compounds and the importance of the acidic group to the activity. This set of data may provide
direction for a strategic procedure to restore the glutamate synaptic transmission; however, further
studies are needed to establish a more complete picture of how these molecules act on the
glutamate transmission, which are in our mind for the next steps.
Keywords: b-Amino acids / b-Amino esters / Excitatory postsynaptic potential / Hippocampus / Synaptic
transmission
Received: June 3, 2017; Revised: August 8, 2017; Accepted: August 10, 2017
DOI 10.1002/ardp.201700179
Additional supporting information may be found in the online version of this article at the publisher’s web-site.
:
metabolic pathway to the natural a-amino acids, being then
metabolically resilient [1, 2].
Introduction
b-Amino acids are molecules closely related to the corre-
sponding natural a-amino acids in that they contain an
ionizable amino group and a carboxy group; however, two
carbons separate these groups instead of one [1]. The main
advantage in designing b-amino acids to obtain bioactive
molecules (such as peptidomimetics or other kind of
molecules) is that they are non-proteinogenic, i.e., they are
not inserted in protein synthesis, and also they can evade the
L-Glutamic acid (Glu, Fig. 1) is the most abundant a-amino
acid in the brain which mediates the most of excitatory
transmission, and it is involved in most aspects of normal brain
functions, such as motor behavior, fear and learning and
memory [3–5]. Glu is synthesized in the cytoplasm and
packaged into synaptic vesicles in the presynaptic terminal
by vesicular glutamate transporters (VGLUTs). Following an
action potential, it activates two families of receptors: the
ionotropic glutamate receptors (iGluRs), N-methyl-D-aspartic
acid, kainic acid and a-amino-3-hydroxy-5-methyl-4-isoxazole
propionic acid receptors (respectively NMDARs, KARs, and
~
Correspondence: Prof. Joao P. S. Fernandes, Departamento de
^
~
^
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Ciencias Farmaceuticas, Universidade Federal de Sao Paulo, Rua
Sao Nicolau 210, 09913-030 Diadema-SP, Brazil.
E-mail: joao.fernandes@unifesp.br
Fax: þ55 11 4044 0500
ꢀAdditional correspondence: Dr. Daniela R. Oliveira,
E-mail: oliveira.dannyy@gmail.com
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Figure 1. Structures of several molecules that interfere in Glu transmission and the LINS04 compounds (2–3). The characteristics
considered in the design are colored; blue: carboxy group; orange: polar group; green: additional lipophilic moiety.
AMPARs), and metabotropic receptors (mGluRs) groups I, II,
and III. Once completed, glutamatergic transmission is mainly
finished by the excitatory amino acid transporters (EAATs),
which take up synaptic Glu into neurons, astrocytes, and
oligodendrocytes. Glutamate reuptake into the brain pre-
vents neuronal excitotoxicity and regulates synaptic transmis-
sion avoiding the establishment of acute CNS injury (e.g.,
stroke, trauma, hypoglycemia) [3, 5–8]. Dysfunctions of Glu
transmission affects normal brain functions with devastating
consequences which could trigger several neurological (e.g.,
epilepsy, Alzheimer’s disease, and Parkinson’s disease) and
psychiatric disorders (e.g., schizophrenia and mood
disorders) [3–6]. There is a great interest for the development
of novel therapeutic agents that interfere in Glu transmission
by binding to the post-synaptic Glu receptors, or by
interfering with membrane transporters.
glutamatergic activity (Fig. 1). More recently, Glu transporters
have also emerged as possible targets to halt or slow the
course of neurological and psychiatric disorders mediated by
Glu, by regulating transmitter release and restoring synaptic
activity [7–10]. Several molecules have been developed as
ligands of Glu transporters. DL-threo-b-Benzyloxyaspartate
(DL-TBOA) [9] is a potent competitive EAATs blocker (IC50
¼
2–70 mM) and has been shown to depress the size of the
evoked field excitatory postsynaptic potential (fEPSP) (10 mM)
in vitro [9–12]. DL-threo-b-Methoxyaspartate (DL-TMOA) is
also an EAAT ligand, but it acts mainly as substrate of such
transporter [10]. Kynurenic acid (KYN) is a selective VGluTs
inhibitor (Ki 1.3 mM) and depresses synaptic transmission at
hippocampal CA1 synapses (IC50 ¼ 130–400 mM) [7, 13–15]. It is
important to stress that Asp itself is not a substrate for VGluTs,
but it is also substrate for EAATs [13–15].
Traditionally, iGluRs have received much attention as
targets to interfere in Glu-mediated processes [9–12].
Molecules as NMDA (and also the a-amino acid L-aspartic
acid (Asp), Fig. 1), AMPA, and KA are classical agonists of such
receptors closely related to the amino acids. mGluRs are also a
target for several bioactive compounds, such as dihydrox-
yphenylglycine (DHPG), a group I mGluRs agonist that
shows that an additional carboxy group is not necessary for
Considering the chemical similarities between the mole-
cules cited above with amino acids, we have screened a first
set of substituted b-amino acids (LINS04 series, Fig. 1) to
investigate their effects on Glu transmission. To the best of
our knowledge, these molecules were not tested yet for this
purpose. Therefore, a preliminary evaluation on synaptic
transmission by LINS04 compounds at hippocampal synapses
from CA1 area was performed.
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The results provide the first evidence that these b-amino acid
derivatives increase synaptic activity at the hippocampus.
Although this study must continue, the preliminary collected
data brought important findings regarding structure–activity
relationships (SAR) data of the compounds. The presence of
an acidic group (i.e., carboxylic acid) seems to be mandatory
to produce an increase in the size of evoked field excitatory
postsynaptic potential, whereas the ester group showed to be
detrimental to the activity. This finding shows the importance
of the acidic group to the interaction to the proteins involved
in Glu transmission, the receptors (mainly iGluRs) or the
membrane transporters (mainly EAATs). However, consider-
ing that the ester group can be biologically hydrolyzed to the
acidic molecules that will be active, they can be considered as
prodrugs [19] for in vivo activation and possibly better cross
the blood–brain barrier. Future pharmacokinetic studies
would define which compounds can adequately reach the
CNS in vivo.
In addition, the 4-chloroaniline group produced less potent
stimulation than the compound with benzylamine group. The
characteristic of the group linked to the b-carbon atom seems
to be important to the activity. Considering the Asp analogs,
NMDA is a potent agonist of NMDAR, while DL-TBOA and
DL-TMOA are not. Moreover, DL-TBOA is an EAAT blocker,
whereas DL-TMOA is a substrate [13, 14]. The role of N-benzyl
or N-(4-chloro)phenyl groups should be better explored yet,
but it may be related to the differences observed in the
activity of 3a and 3b.
Results and discussion
The LINS04 compounds were synthesized as shown in
Scheme 1. The b-enamino esters were prepared by reacting
ethyl acetoacetate with corresponding amine [16]. The yields
for compounds 1a and 1b were 97 and 60%, respectively. The
lower yield of the latter can be attributed to the low
availability of the electrons of aniline to attack the ketone
carbonyl group of ethyl acetoacetate. As can be observed in
the experimental procedure, the synthesis of compound 1a
was carried out in ultrasonic conditions at 25°C by simply
mixing the reagents in equimolar amount with catalytic (10%)
of AcOH. This procedure did not show convenient to prepare
compound 1b, and then classical reflux method was used.
The b-enamino esters were then converted to the
corresponding b-amino esters LINS04005 (2a) (75%) and
LINS04006 (2b) (70%) using STAB as reducing agent, prepared
in situ [17]. As STAB is a moderate and highly selective
reducing agent for imine/enamine group, the ester group
could be easily preserved. Finally, these compounds were
hydrolyzed by refluxing with 10% NaOH in THF [18], to give
the compounds LINS04008 (3a) and LINS04009 (3b) with 85
and 80% yields, respectively.
To investigate the effects of b-amino acid derivatives on
synaptic transmission at hippocampal CA1 synapses, we used
field recordings in rats hippocampal slices. Application of 3a
increased the size of of evoked field excitatory postsynaptic
potential (fEPSP) in the hippocampal-CA1 synapses in a
concentration-dependent manner, producing a curve with a
maximal increase of 44.97% (Table 1) and EC50 value of
91.32 mM (Fig. 2A). Compound 3a has the greatest potency
on the dose–response curve. The effects of 3b also increased
fEPSP in hippocampal-CA1 synapses; the curve displayed a
maximal increase of 32.72% (Table 1) and EC50 value of
29.97 mM (Fig. 2B). Interestingly, application of compounds 2a
and 2b did not affect the transmission (Table 1).
To investigate some of the possible mechanisms involved in
the enhancement of synaptic activity by 3a, we performed
some initial assays in the presence and absence of DL-TBOA
and KYN (Fig. 3). Several works have shown that DL-TBOA and
KYN depress the size of fEPSP in hippocampal-CA1 synapses,
mainly by acting as iGluRs antagonists [9–15]. We observed
that when 100 mM of 3a was added along with 10 mM of
DL-TBOA (Fig. 3A), significant reduction on fEPSP was
Scheme 1. Synthesis of compounds 1–3.
Reagents and conditions. (a) BnNH2 (1 eq.),
AcOH (0.1 eq.), US 0.5 h or 4-chloroaniline
(1 eq.), AcOH (0.1 eq.), EtOH, reflux, 3 h; (b)
STAB (3 eq.), AcOH, 2 h; (c) NaOH 40%, THF,
reflux, 12 h.
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Table 1. Activity of tested compounds in fEPSP recording
in CA1 hippocampal slices.
in Fig. 2B. Though, considering that DL-TBOA and KYN are
iGluRs antagonists [7, 14, 15], the obtained data suggest that
the effects of 3a on fEPSP may be attributed to possible
agonism on iGluRs, albeit more specific experiments must be
done to confirm this hypothesis.
fEPSP max.
Compounds
EC50 mM (95%CI)
(% ꢁSD)
2a
2b
3a
3b
NA
NA
2 (ꢁ2)
The most important contribution of this work is the
investigations in the effects of LINS04 series on synaptic
transmission at hippocampal CA1 synapses which were
unpublished until this report. Our study has revealed that
3a and 3b increased the synaptic activity, similar to those seen
in the natural amino acids (Glu and Asp) [20, 21]. These data
provide information from novel prototypes for a strategic
design of molecules to restore synaptic activity, especially
mediated by AMPAR and NMDAR. Clearly, further studies are
needed to establish a more complete picture of how these
molecules contribute to synaptic activity in both health
conditions and neurological/psychiatric disorders, which are
in our mind for the next steps.
2 (ꢁ2)
91.32 (63.51–131.30)
29.97 (16.71–53.74)
44.97 (ꢁ2.50)
32.12 (ꢁ3.12)
EC50, effective concentration on 50% of maximum fEPSP
observed; NA, not active.
observed. On the other hand, after DL-TBOA washing out, 3a
increased again the size of fEPSP, as observed previously in
Fig. 2A. Considering that DL-TBOA acts as inhibitor of EAATs in
addition to some iGluRs blocker activity [14], our data suggest
that 3a can also be ligand of the EAATs, acting as substrate,
which competed by these transporters leading to higher
DL-TBOA concentration in the synapses. This effect led to
increased activity on iGluRs by DL-TBOA, and consequent
reduction on fEPSP recordings.
Experimental
Chemistry
General
Conversely, 3a (100 mM) did not affect the depression
produced by 100 mM of KYN (Fig. 3B). After KYN washing out,
3a increased again the size of fEPSP by the same way observed
The chemicals were provided by Sigma–Aldrich, Merck
(Darmstadt, Germany) and LabSynth (Diadema, Brazil) in
Figure 2. Effects of 3a and 3b at hippocampal
synapses from CA1 area. Application of 3a (A)
and 3b (B) (1.0–1000 mM) causes a significant
and reversible increase in the size of the
evoked field excitatory postsynaptic poten-
tial (fEPSP) (n ¼ 5). The experiments were
conducted in presence of picrotoxin (50 mM).
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Figure 3. Effects of 3a at hippocampal
synapses from CA1 area in presence of
DL-TBOA (A, single experiment) and KYN
(B, n ¼ 4). Application of 3a (100 mM)
together with DL-TBOA (10 mM) causes
a
reduction of the size of the evoked fEPSP,
while no influence was observed for its
application with KYN (100 mM). The experi-
ments were conducted in presence of picro-
toxin (50 mM).
adequate purity grade, and used without further purification.
1H and 13C NMR spectra were recorded in a Bruker Ultrashield
300 spectrometer, operating at 300 and 75 MHz, respectively,
using the indicated deuterated solvent and internal standard.
Chemical shifts are reported in parts per million (ppm, d units).
Coupling constants (J) are reported in units of hertz (Hz), if
applicable. The high resolution mass spectra (HRMS) were
obtained through direct injection after electron-spray ioniza-
tion in positive mode (ESIþ) in a MicroTOF from Bruker
Daltonics mass spectrometer. Stock solutions of the tested
compounds were prepared by dissolving in purified water
prior to the experiments.
Synthesis of compounds 2
In a flask, 4 mL of acetic acid and 4 mmol (0.15 g) of sodium
borohydride were added and stirred at 0°C until the final
of hydrogen evolution. After this, 2 mmol of compound 1
was added to the reaction mixture, and the reaction
was kept at 25°C for 2 h. The solvent was evaporated
under reduced pressure, and 10 mL of saturated K2CO3
solution was added. The mixture was extracted with
2 ꢂ 10 mL of dichloromethane, and the organic layer
was dried over anhydrous Na2SO4, and the solvent
evaporated. Crude products were purified by column
chromatography in silica gel, using hexane/ethyl acetate
(1:1) as eluent.
The InChI codes of the investigated compounds together
with some biological activity data are provided as Supporting
Information. The 1H NMR spectra of compounds 3a and 3b are
also provided as Supporting Information.
2a: Yellowish liquid (75%); 1H NMR (300 MHz, CDCl3, TMS,
ppm) d 7.35–7.21 (m, 5H), 3.82–3.75 (m, 2H), 3.16 (sext, 1H,
J ¼ 6.4 Hz), 2.49 (dd, 1H, J ¼ 15.2, 7.0 Hz), 2.37 (dd, 1H, J ¼ 15.2,
5.9 Hz), 1.37 (br.s, 1H), 1.25 (t, 3H, J ¼ 7.2 Hz), 1.16 (d, 3H,
J ¼ 6.3 Hz); 13C NMR (75 MHz, CDCl3, TMS, ppm) d 171.3, 140.6,
128.2, 127.2, 127.1, 60.8, 51.9, 48.0, 40.7, 19.7, 14.0; HRMS
calculated 221.1415; found 222.1517 [MþHþ].
Synthesis of compounds 1
In a flask, 5 mmol (0.65 g) of ethyl acetoacetate, 5 mmol of the
corresponding amine (benzylamine or 4-chloroaniline), and
0.5 mmol (0.03 g) of acetic acid were added. The reaction was
maintained in the conditions presented in Table 2. Ethanol
(10 mL) was added to the final mixture, which was dried over
anhydrous Na2SO4, and the solvent evaporated. Crude
products were purified by column chromatography in silica
gel, using hexane/ethyl acetate (8:1) as eluent. Spectral data
were in agreement with previous report from literature [16].
1
2b: Yellowish liquid (70%); H NMR (300 MHz, CDCl3, TMS,
ppm) d 7.15–7.08 (m, 2H), 6.58–6.51 (m, 2H), 4.14 (q, 2H,
J ¼ 7.2 Hz), 3.95–3.82 (m, 1H), 2.63 (dd, 1H, J ¼ 15.0, 5.5 Hz),
2.42 (dd, 1H, J ¼ 15.0, 6.8 Hz), 1.26 (d, 3H, J ¼ 7.0 Hz), 1.25 (t,
3H, J ¼ 7.2 Hz); 13C NMR (75 MHz, CDCl3, TMS, ppm) d 171.5,
143.9, 128.9, 126.2, 119.3, 60.7, 45.9, 40.8, 20.7, 14.1; HRMS
calculated 241.0869; found 242.0971 [MþHþ].
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Table 2. Conditions to prepare compounds 1a and 1b.
Compound
Condition
Temperature (°C)
Time (h)
Yield (%)
1a
1b
Ultrasound
Conventional
25
90
0.5
3
97
60
Synthesis of compounds 3
Extracellular field recordings
To 2 mmol of compounds 2 in 5 mL of tetrahydrofuran, was
added 2 mL of aqueous NaOH 40%. The reaction was
maintained under vigorous stirring for 12 h at 90°C. The
solution was then neutralized with aqueous HCl, and
the solvent was removed under reduced pressure to dryness.
The crude solid was extracted with ethyl acetate, dried over
anhydrous Na2SO4, and the solvent evaporated again. The
product was purified by precipitation in ethyl acetate/hexane
mixture.
Field excitatory postsynaptic potentials (fEPSPs) were evoked
at 0.033 Hz using bipolar stimulating electrodes (0.05 mm
diameter) and recorded using glass micropipettes filled with
3 M NaCl (resistance 3–6 MΩ). Stimulating electrode was
placed in the Schaffer collateral and the recording electrode
was placed in the stratum radiatum (SR) of CA1 area. Once
responses were found, slices were fully submerged in
oxygenated aCSF perfused in a rate of 2 mL/min. A total of
50 mM of picrotoxin was also added to the perfusate in
all experiments. Stimulation intensity was selected that
produced responses that were around 50% maximal, and
experiments began after stable baseline response was
recorded for a period of at least 30 min. Responses were
measured and recorded online using WinLTP software
(version 2.20a; WinLTP Ltd. and The University of Bristol,
Bristol, UK). Compounds were applied by addition to perfuse
by 20 min.
3a: White solid (85%); 1H NMR (300 MHz, D2O, DSS, ppm) d
7.43–7.36 (m, 5H), 4.26–4.09 (m, 2H), 3.56–3.43 (m, 1H), 2.48 (d,
2H, J ¼ 6.4 Hz), 1.30 (d, 3H, J ¼ 6.9 Hz); 13C NMR (75 MHz, D2O,
DSS, ppm) d 176.1, 140.5, 128.1, 127.0, 126.9, 51.9, 47.6, 42.3,
19.5; HRMS calculated 193.1103; found 192.1205 [MꢃHþ].
3b: Yellowish liquid (80%); 1H NMR (300 MHz, D2O, DSS,
ppm) d 7.25–7.15 (m, 2H), 6.83–6.73 (m, 2H), 3.81–3.65 (m, 1H),
2.49 (dd, 1H, J ¼ 14.1, 5.1 Hz), 2.10 (dd, 1H, J ¼ 14.1, 8.4 Hz),
1.13 (d, 3H, J ¼ 6.4 Hz); 13C NMR (75 MHz, D2O, DSS, ppm)
d 176.1, 144.0, 128.9, 126.2, 119.3, 45.9, 42.3, 20.6; HRMS
calculated 213.0556; found 212.0658 [MꢃHþ].
Data analysis
Data were normalized to the mean slope recorded during the
30 min baseline. All data are presented as mean ꢁ standard
error of the mean (SEM) and EC50 are presented with 95%
confidence intervals in parentheses. Concentration–response
were plotted using GraphPad Prism software (version 6.0).
Standard agonist concentration–response curves were fitted
with the following equation: Y ¼ Ymin þ (Ymax ꢃ Ymin)/
(1 þ 10(logEC50-X)), where X is logarithm of the concentration
of the agonist and Y is the percentage inhibition. Ymin was
constrained to zero for curves.
Biological assays
Animals
Male Wistar rats 4 to 5-week-old were obtained from Charles
River, UK. All animals were housed under 12 h light/dark cycle,
and experiments were performed in the light phase of the
cycle. Animals were allowed access to food and water ad
libitum, and all procedures were carried out in accordance
with the Animals (Scientific Procedures) Act 1986.
Hippocampal slice preparation
The authors would like to thank Conselho Nacional de
ꢀ
ꢀ
Rats were killed by cervical dislocation and decapitation, and
the brains were rapidly removed and placed into ice-cold
artificial cerebrospinal fluid (aCSF; in mM: 124 NaCl, 3 KCl, 26
NaHCO3, 1.4 NaH2PO4, 1 MgSO4, 10 D-glucose, 2 CaCl2)
continuously oxygenated with 95% O2 and 5% CO2.
Parasagittal slices (400 mm) containing the hippocampal
formation were prepared in ice-cold, oxygenated aCSF using
Vibroslicer and placed in a Petri dish containing fresh-
oxygenated aCSF. The hippocampus was dissected from
these slices and area CA3 was removed to reduce the risk of
contaminating the field excitatory post-synaptic potential
(fEPSP) recording via indirect pathway to area CA1.
Hippocampal slices were left to rest for ꢄ2 h before
being transferred to the recording chamber maintained at
27–30°C, where they were continuously perfused with
oxygenated aCSF at a rate of 2 mL/min [22].
Desenvolvimento Cientıfico e Tecnologico, of the Ministry of
Science, Technology and Innovation of Brazil (CNPq, grant
~
455411/2014-0) and Sao Paulo State Research Foundation
(FAPESP, grant 2013/20479-9) for providing financial support
to JPSF’s lab. DRO also thanks CNPq for the post-doctoral
training grant (229217/2013-3).
The authors have declared no conflict of interest.
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